The present invention relates to a process and use of at least one Si, Ge or Sn comprising catalyst for phosphorylation, in particular phosphitylation, of hydroxyl groups. A phosphorous compound is added to a hydroxyfunctional compound having at least one hydroxyl group and said addition yields in the presence of said catalyst a phosphorous reaction product having at least one Oxe2x80x94P bond.
The manufacture and use of phosphorous compounds, such as phosphates, phosphites and phosphides, are of substantial importance in areas including various animal die, fertilisers, detergents, pharmaceuticals, plasticisers, antioxidants, flame retardants and the like.
Phosphorylation of hydroxyfunctional compounds is known to be performed using phosphorous acids, whereby the phosphorus containing groups react with hydroxyl groups and other similar procedures.
Phosphorylations comprising a reaction between for instance an amide of a phosphorous acid and a hydroxyfunctional compound, as illustrated by the simplified reaction scheme (a) below 
wherein each R independently can be alkyl, cycloalkyl, aryl, alkoxy, cycloalkoxy, aryloxy, thiolo and the like, proceed very slowly and with exceptionally low yield, often as low as 20% or less, and a catalyst is normally used. A frequently used catalyst is tetrazole. derivatives thereof and structural analogues. The yield is thereby increased, but still very low, normally less than 50%. The use of tetrazole and its derivatives as catalysts exhibit, besides the low yield a number of drawbacks such as
the amount of tetrazole must be optimised in every case,
excess of tetrazole must be used,
formation of side products, usually derivatised from disproportionations,
problems caused by separation, and
freshly sublimed tetrazole must be used,
tetrazole is very expensive making large scale syntheses impossible
tetrazole is difficult, inconvenient and hazardous to handle.
Through the present invention, it has quite unexpectedly been found that a range of compounds, not previously employed as catalysts in phosphitylations and phosphorylations, substantially improve reaction time and yield. The yield is for instance in comparison to tetrazole increased from less than 50% to 80-100%, normally 90-95%.
The present invention refers to a process for phosphorylation, in particular a phosphitylation, of hydroxyl groups and use of at least one Si, Ge or Sn comprising catalyst during said process, whereby a phosphorous compound such as an amide of a trivalent phosphorous acid reacts with a hydroxyfunctional compound yielding a phosphorous reaction product having at least one Oxe2x80x94P bond. The process is performed in the presence of at least one catalyst of general formula (1):
(R1)nX(R2)4xe2x88x92nxe2x80x83xe2x80x83Formula (1)
wherein
i) each R1 independently is
a) hydrogen,
b) at least one alkanyl, alkenyl, alkynyl, cycloalkanyl, cycloalkanyl, cycloalkynyl, aryl, alkanylaryl, alkenylaryl, alkynylaryl, trityl, alkoxy, cycloalkoxy, aryloxy or amino group,
c) a polymeric moiety derived from a carbon polymer or copolymer,
d) at least one halogenated and/or silylated alkanyl, alkeninl, alkynyl cycloalkanyl, cycloalkenyl, cycloalkynyl, aryl, alkanylaryl, alkenylaryl, alkynylaryl, trityl, alkoxy, cycloalkoxy, aryloxy or amino group, and/or
e) a polymeric moiety derived from a halogenated and/or silylated carbon polymer or copolymer;
ii) X is Si, Ge or Sn;
iii) each R2 independently is a leavening group and is
a) F, Cl, Br or l; or
b) a sulphonate group of general formula (2) 
xe2x80x83wherein R3 is F, Cl, Br, I, alkanyl, alkenyl, alkynyl, aryl, arylalkanyl, arylalkenyl, arylalkynyl, haloalkanyl, haloalkenyl, haloalkynyl, haloaryl, haloarylalkanyl, haloarylalkenyl, haloarylalkynyl, arylhaloalkanyl, arylhaloalkenyl, arylhaloalkynyl or a group of formula CR4, wherein R4 is F3, Cl3, Br3 or I3;
iv) n is 1, 2 or 3.
The reaction performed during the process and activated by the compound of Formula (I) can be exemplified by below reaction scheme (b) illustrating the phosphitylation of thymidine using trimethylchlorosilane as catalyst:

Activation by a catalyst in accordance with the present invention requires normally one equivalent or less. The reaction is fast. often 30 minutes to 2 hours at 20xc2x0 C., and free of side products. The yield is excellent, in most cases 95-100% and the resulting products are essentially pure requiring no further purification,
In preferred embodiments of the invention is each R1 individually methyl, ethyl, butyl, propyl, pentyl, hexyl, heptyl, octal, nonyl, decyl, methylethyl, methylbutyl, methylisobutyl, methylpropyl, methylisopropyl, methyloctyl, methylphenyl, methyltrityl, allylmethyl, allylethyl, ethylbutyl, ethylisobutyl, ethylpropyl, ethylisopropyl, butylphenyl, butylmethoxyphenyl, ethoxy, propoxy, butoxy, ethoxymethyl, ethoxyethyl, thexylmethyl, phenyl, benzyl, xylyl, thexyl, thexylethyl, methyltrityl, butylmethylene, butylphenoxymethyl, methoxymethyl, vinyl, vinylmethyl, vinylethyl, vinylethoxy, cyanomethyl, cyanoethyl, halomethyl, haloethyl, halobutyl, halopropyl, halopentyl, halohexyl, haloheptyl, haloctyl, halononyl, halodecyl, halophenyl, halobenzyl, haloxylyl, halothexyl, methylhalohexyl, halophenylmethyl, butylhalophenylmethyl, halovinyl, vinylhalomethyl or vinylhaloethyl. At least one R1 can in these and other preferred embodiments can be a moiety derived from, for example an analogue of, an organic polymer or copolymer, such as polyethylene, a polystyrene, a polyether or a polyester, or any analogues thereof, which polymer optionally is silylated and/or halogenated. X is in these and other especially preferred embodiments preferably Si.
Employed catalyst is in especially preferred embodiments a trialkylhalosilane, such as a trialkylchlorosilane, trialkyliodosilane, trialkylbromosilane or trialkylfluorosilane preferably selected from the group consisting of trimethylchlorosilane, triethylchlorosilane, tributylchlorosilane, tripropylchlorosilane, trimethyliodosilane, triethyliodosilane, tributyliodosilane, tripropyliodosilane, trimethylbromosilane, triethylbromosilane, tributylbromosilane, tripropylbromosilane, trimethylfluorosilane, triethylfluorosilane, tributylfluorosilane, tripropylfluorosilane.
Further compounds, advantageously being used as catalysts in accordance with the present invention, of Formula (I) wherein X is Si are suitably exemplified by trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, trimethylsilyltrichloroacetate, trimethylsilyltrifluoroacetate, allyldimethylchlorosilane, bromomethyldimethylchlorosilane, tert-butyldimethylchlorosilane, N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide. N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-trimethylsilyl-heptafluorobutyramide, N-methyl-N-trimethylsilyltrifluoroacetamide, trimethylsilyltrifluoromethanesulphonate, tert-butyldimethylsilyltrifluoromethanesulphonate, tert-butyldiphenylchlorosilane, tert-butyl-methoxy-phenylbromosilane, chloromethyldimethylchlorosilane, dimethyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)chlorosilane, dimethylphenylchlorosilane, dimethyltritylbromosilane, diphenylmethylchlorosilane, isopropyldimethylchlorosilane, (pentafluorophenyl)dimethylchlorosilane, thexyldimethylchlorosilane, thexyldimethylsilyl trifluoromethanesulphonate, tributylchlorosilane, triethylchlorosilane, trithylsilyltrifluoromethanesulphonate, triisopropylchlorosilane, triisopropylsilyltrifluoromethanesulphonate, triphenylchlorosilane, tripropylchlorosilane, di-tert-butyldichlorosilane, di-tert-butylsilyl bis(trifluoromethanesulphonate), diethyldichlorosilane, diisopropylsilyl-bis(trifluoromethanesulphonate), dimethyldichlorosilane, diphenyldichlorosilane, methylphenyldichlorosilane, dimethyloctylchlorosilane, dodecyltrichlorosilane, thexyldimethylsilyl-trifluoromethanesulphonate, thexyl-dimethylchlorosilane, trichlorosilan, 3-(triethylsilyl)propyl-trimethylammoniumchloride, trimethylsilylbromoacetate, trimethylsilylchlorosulphonate, 2-(trimethylsilyl)ethoxymethyl chloride, tri(dimethylamino)sulphonium-difluorotrimethylsilicate and 1,3-bis(chloromethyl)-1,1,3,3-tetramethyldisilazane.
One or more solvents are suitably present during the process of the present invention. The solvent is preferably selected from the group consisting of aliphatic solvents, cycloaliphatic solvents, aromatic solvents, 1,3-dioxanes, 1,3-dixolanes, 1,3,5-trioxepanes, furans and/or haloalkanes, such as hexane, toluene, xylene, tetrahydrofuran, dichloromethane and acetonitrile.
The process of the invention and the catalyst used therein are suitable for phosphorylation, in particular phosphitylation, of hydroxyfunctional compounds such as mono, di, tri and polyfunctional alcohols, monosaccharides, disaccharides, polysaccharides, sugar alcohols, cyclodextrins, inositols, nucleosides, terpenoids, lipids, phenols, polyphenols, hydroxyfunctional polymers, hydroxyfunctional carboxyl, acids and/or derivatives of said hydroxyfunctional compounds. The hydroxyfunctional compound is advantageously selected from the group consisting of:
a) pentoses, hexoses and heptoses such as D/L-ribose, D/L-arabinose. D/L-xylose, D/L-lyxose, D/L-allose, D/L-altrose, D/L-alucose, D/L-mannose, D/L-gulose, D/L-idose, D/L-galactose, D/L-talose, D/L-glucoheptose. D/L-mannoheptose, D/L-ribulose, D/L-xylulose D/L-psicose, D/L-fructose, D/L-sorbose, D/L-tagatose, D/L-sedoheptulose and/or derivatives of said pentoses, hexoses and heptoses,
b) pentitols, hexitols and heptitols such as D/L-ribitol, D/L-arabinitol, D/L-xylitol, D/L-lyxitol, D/L-allitol, D/L-altritol, D/L-glucitol, D/L-mannitol, D/L-gulitol, D/L-iditol, D/L-galactitol, D/L-talitol, D/L-glucoheptitol, D/L-mannoheptitol, D/L-ribulitol, D/L-xylulitol, D/L-psicitol, D/L-fructitol, D/L-tagatitol, D/L-sedoheptulitol and derivatives of said pentitols, hexitols and heptitols,
c) anhydropentitols, anhydrohexitols, anhydroheptitols and derivatives thereof,
d) celobioge, maltose, lactose, saccharose, gentobiose, melibiose, trehalose, turanose and derivatives thereof,
e) starch, glycogen, cellulose, dextran, tunicine and/or derivatives thereof, and
f) myo-inositol, cis-inositol, epi-inositol, allo-inositol, neo-inositol, muco-inositol, D/L-chiro-inositol, scyllo-inositol and derivatives of said inositols,
g) 5-ethyl-5-methanol-1,3-dioxane, 2-ethyl-2-butyl-1,3-propanediol, neopentyl glycol, glycerol, trimethylolpropane, trimethylolethane, pentaerythritol, diglycerol, ditrimethylolpropane, ditrimethylolethane, dipentaerythritol, tripentaerythritol and derivatives thereof,
h) 2,2-dimethylolpropionic acid, xcex1,xcex1-bis-(hydroxymethyl)butyric acid, xcex1,xcex1,xcex1-tris(hydroxymethyl)acetic acid, xcex1,xcex1-bis-(hydroxymethyl)valeric acid, xcex1,xcex1-bis(hydroxy)propionic acid, 3,5-dihydroxybenzoic acid, xcex1,xcex2-dihydroxypropionic acid, heptonic acid, citric acid, tartaric acid, dihydroxymaloic acid, gluconic acid and derivatives thereof.
As used herein, the term xe2x80x9cD/Lxe2x80x9d is used to indicate the various isomers of the particular compound, including any mixture thereof. For example, xe2x80x9cD/L-ribosexe2x80x9d denotes D-ribose, L-ribose or any combination thereof, including the racemic mixture.
The hydroxyfunctional compound can also suitably be a dendritic or hyperbranched macromolecule. Hyperbranched and dendritic macromolecules normally consist of an initiator or nucleus having one or more reactive sites and a number of surrounding branching layers optionally being chain terminated. The layers are usually called generations, whereby each generation comprises one or more branches, usually called dendrons. A macromolecule suitable for a phosphitylation according to the present invention can be composed of a monomeric or polymeric nucleus to which 1-100, preferably 1-20, generations consisting of at least one monomeric or polymeric chain extender are added. The chain extender has at least one, preferably at least two, reactive hydroxyl groups and at least one reactive carboxyl group. The terminal functions of yielded macromolecule is, prior to the optional chain termination, substantially hydroxyl groups. An optional chain termination is performed in such a manner and to such a degree that the macromolecule finally has at least one terminal hydroxyl group. The nucleus may be a compound, such as an alcohol, a polyalcohol, a glycidyl ester, a glycidyl ether or the like having at least one reactive hydroxyl or epoxide group. In further embodiments, the nucleus may be a metal ion or an organometallic compound being hydroxy and/or epoxide functional or the like.
Hyperbranched and dendritic macromolecules (dendrimers) can generally be described as three dimensional highly branched molecules having a tree-like structure. Dendrimers are highly symmetric, while similar macromolecules designated as hyperbranched may to a certain degree hold an asymmetry, yet maintaining the highly branched tree-like structure. Dendrimers can be said to be monodisperse variations of hyperbranched macromolecules. The composition of hyperbranched dendritic or near dendritic macromolecule can be illustrated by below simplified Formula (3.1) and (3.2) illustration a hyperbranched macromolecule (Formula 3.1) and a dendron (Formula 3.2) being part of the macromolecule. Regard is not taken to any three dimensional structure. The macromolecule has two generations of chain extenders (A and B) having 3 and 4 reactive sites. The reactive sites are one carboxyl group, reacted with the nucleus (Y), and hydroxyl groups. The macromolecule is partly chain terminated by means of a chain terminator (T). The nucleus or initiator (Y) is as previously defined. 
The hydroxyfunctional compound can, furthermore, be a dendron of for instance general formula (4) R12(OOR13)q(OOR14)y(OOR15)z, wherein each R12, R13, R14 and R15 independently is alkanyl, alkenyl, alkynyl, cycloalkanyl, cycloalkenyl, cycloalkynyl, aryl, alkanylaryl, alkenylaryl or alkynylaryl, q is an integer and at least 1, y is 0 or an integer and at least 1 and wherein z is an integer between 1 and 25, preferably between 1 and 10. A suitable dendron can be exemplified by self condensated 2,2-dimethylolpropionic acid, whereby a suitable number of moles of said compound is condensated (esterified) at a temperature of for instance 150-25xc2x0C. 2,2-Dimethylolpropionic acid has two hydroxyl groups and one carboxyl group and one molecule of the compound can thus react with two other molecules, whereby a highly branched chain consisting of esterified 2,2-dimethylolpropionic can be prepared.
The phosphorous compound used in the phosphorylation process is advantageously an amide of a phosphorous acid containing trivalent phosphorus, which compound is of general formula (5), (6) or (7), R5R6PNR7R8, R6P(NR7R8)2 or P(NR7R8)3, wherein each R5 and R6 independently is an alkyl, a cycloalkyl, an aryl, an alkoxy, a cycloalkoxy, an aryloxy, a thiolo or an amido group and wherein each R7 and R8 independently is an alkyl, a cycloalkyl or an aryl group. The phosphorous compound can alternatively be of general formula (8) or (9), (R9CH2O)2PNR10R11 or (NCCH2CH2O)2PNR10R11, wherein each R9 independently is aryl or alkaryl and wherein each R10 and R11 independently are C1-C12 alkyl. Said phosphorous compounds can be exemplified by neopentylene-N,N-dimethylphosphoroamidite, o-phenylene-N,N-diisopropylphosphoroamidite, di-(2-cyanoethyl)-N,N-diisopropylphosphoroamidite, 2-cyanoethyl-N,N-diisopropylfluorophosporoamidite, dibenzyl-N,N-diethylphosphoroamidite and hexamethylphosphorotriamide.
A phosphitylation process according to the present invention is preferably perform, at a temperature of xe2x88x9280xc2x0 C. to 120xc2x0 C. such as xe2x88x9210xc2x0 C. to 80xc2x0 C. or 0xc2x0 C. to 40xc2x0 C., using a catalyst amount corresponding to 0.01 to 3, preferably 0.05 to 1 and most preferably 0.1 to 0.5, equivalents calculated on phosphorous equivalents. The amount of catalyst is normally between 5% and 80%. A suitable and preferred order of addition is 1 the phosphorous compound or compounds, 2 the hydroxyfunctional compound or compounds and 3 the catalyst or catalysts
The phosphorylated, in particular phosphitylated, reaction product obtained in the process and by using the catalyst of the present invention can optionally be further processed. Trivalent phosphorus included in the reaction product can for example be oxidised to pentavalent phosphorus using an oxidising agent, such as a peroxide, a hydroperoxide, a peracid, or by means of sulphur transferring reagents including elemental sulphur. Phosphites can thus be transformed into phosphates yielding for instance pharmaceutically active and important trisphosphates of monosaccharides and inositols. Furthermore, xcex2-cyanoalkyl groups included in the phosphorylated product can be eliminated in the presence of a base, such as potassium hydroxide, sodium hydroxide or an amine and benzyl groups by means of a hydrogenolysis.
The present invention makes it possible to employ simple phosphitylation reagents of for instance formula (8) or (9) for phosphitylation of 3xe2x80x2-protected nucleosides, 5xe2x80x2-protected nucleosides and other alcoholic compounds of biological importance, such as sugars, terpenoids and lipids. Oxidisation of phosphites to phosphates, optional removal of xcex2-cyanoalkyl and benzyl groups, result in a phosphate yield of normally more than 90%.
Further application areas of the process of present invention and catalyst used therein are
preparation of oligomeric and polymeric dendrons from polyols by a suitable choice of phosphitylation reagent,
preparation of antioxidants containing a nucleus of trivalent phosphorus,
preparation of intermediates containing trivalent phosphorus, which can be converted into tetravalent or pentavalent structures resulting in important biophosphates and their structural analogues as well as material improving components, such as plasticisers and flame retardants,
preparation of olefinic monomers containing trivalent and pentavalent phosphorus, which monomers when heated in the presence of for instance benzoyl peroxide give flame retardant solids. and
preparation of detergents.